6 - cycloalkylguanamines,preparations and methods for treating inflammatory conditions therewith



United States Patent 3,478,026 6 CYCLOALKYLGUANAMINES, PREPARATIONS AND METHODS FOR TREATING INFLAMMA- TORY CONDITIONS THEREWITH Takashi Enkoji, Park Forest, 111., and Edward M. Levine, Buffalo, N.Y., assignors to Armour Pharmaceutical Company, Chicago, [1]., a corporation of Delaware No Drawing. Filed Aug. 16, 1967, Ser. No. 660,919 Int. Cl. C07d 55/20; A61k 27/00 U.S. Cl. 260-2493 4 Claims ABSTRACT OF THE DISCLOSURE 6-cycloalkylguanamines are disclosed wherein the cycloalkyl radical contains from 3 to 10* carbon atoms. The compounds are of the class of 6-(substituted)guanamines, also called 2,4-diamino-s-triazines, and are useful in forming preparations for the therapeutic treatment of inflammatory conditions. Exemplary of the compounds disclosed is '6-cyclopropylguanamine. The non-toxic acid addition salts of the compounds are also therapeutically useful.

This invention relates to new chemical compounds, to pharmaceutical preparations containing such compounds and to therapeutic methods of using such compounds in treating inflammatory conditions.

As used herein, the treatment of inflammatory conditions refers to the inhibition or control of various aspects of inflammation and, more particularly, to a remission of the symptoms and signs of inflammatory diseases, such for example, as rheumatoid arthritis, lupus erythematosus disseminatus, ankylosing spondylitis, psoriatic arthritis, gouty arthritis, fibromyostis, osteoarthritis, bursitis, scleroderma and other inflammatory conditions such as bronchial asthma, pulmonary emphysema, pulmonary fibrosis, inflammation resulting from infection, inflammation resulting from tissue injury, inflammation resulting from allergy, skin disorders, including atopic dermatitis, contact dermatitis, dermatitis herpetiformis, angioedema, urticaria, and exfoliative dermatitis, pemphigus, inflammatory eye diseases including keratitis, allergis conjunctivitis, nongranulomatous iritis, iridocyclitis, choroiditis, uveitis, chorioretinitis, nephrodic syndrome, and the like.

Considering rheumatoid arthritis as illustrative of the inflammatory diseases, including those attended by both chronic and acute inflammatory conditons, rheumatoid arthritis is generally defined as a chronic, though nonfatal disease, of uncertain origin, which affects one or more of the patients joints by redness, pain, heat and/ or swelling. Frequently, inflammation in a joint causes deformity and loss of function.

For purposes of this disclosure, the foregoing shall be referred to as inflammatory diseases and the like and inflammation shall refer to the occurrence of one or more of the symptoms: redness, pain, heat and swelling.

The traditional approach to therapeutic treatment of the inflammatory diseases such as rheumatoid arthritis, heretofore comprised administering to the afllicted patient a variety of analgesics and antipyretics and even narcotics.

In more modern times, greater attention has been given to the use of hormones and steroids having a systemic effect, for example, ACTH, cortisone, cortisone acetate, hydrocortisone, prednisolone, and the prednisolone derivatives. In addition, the hormones and steroids have been combined with analgesics and antipyretics to provide further therapeutic approaches.

From the many approaches available, it is generally accepted that the most desirable result, when the patient can assimilate and tolerate the drug, is achieved by the administration of the glucocorticoid steroids.

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However, extreme care must be exercised with the administration of these steroids because they are known to cause undesirable changes in bone structure, in electrolyte and in carbohydrate metabolism and to induce moon-face, hirsutism, hypokalemia, peptic ulcers, hypertension, acne, amenorrhea, sever mental disturbances and suppression of the adrenocortical pituitary function.

Furthermore, the glucocorticoid steroids cannot be used except with extreme caution in the presence of active tuberculosis, diabetes mellitus, osteoporosis, chronic psychotic reactions, predisposition to thrombophlebitis, hypertension, congestive heart failure or renal insufficiency. In addition, the corticosteroids are not generally acceptable to patients in early stages of pregnancy. Further, corticosteroids should not usually be administered in the presence of infection because they inhibit fibroplasia and therefore, can mask the dissemination of the causative organism. Still further, in many cases of inflammatory disease, such as rheumatoid arthritis, the corticosteroids are ineffective, that is, the patients are resistant to steroid therapy.

Thus, in spite of the promise the glucocorticosteroids bring to the field of treating the inflammatory diseases, they are fraught with suflicient disadvantages to demand that research continue for therapeutic agents having equal or better properties and substantially less, if not none, of the undesirable side effects.

It is also desirable that anti-inflammatory agents be made available which may be administered orally and which are very low in toxicity.

The present invention is based upon our discovery of 6-cycloalkylguanamines of the type having the structural formula wherein R is cycloalky-l having a carbon content of C to C We have also discovered that these compounds, when employed in pharmaceutical preparations, possess definite anti-inflammatory properties. As will be shown, these compounds are potent anti-inflammatory agents, may be ad ministered orally, have a surprisingly low degree of toxicity, and exhibit substantially none of the side effects which characterize steroid therapy.

Accordingly, a principal object of the present invention is to provide new and useful chemical compounds which, when employed in pharmaceutical preparations for therapeusis, have anti-inflammatory properties and are especially well suited for providing relief and comfort for patients afflicted with chronic and acute inflammatory conditions.

Another object of the present invention is to provide new and useful chemical compounds which, when employed in pharmaceutical preparations for therapeusis, are effective to treat inflammatory conditions while being relatively free from adverse side effects particularly those which have heretofore characterized the use of glucocorticosteroids.

Still another object of the present invention is to provide new and useful chemical compounds which, when employed in pharmaceutical preparations for therapeusis, are characterized by low toxicity and permit the treatment of the signs and symptoms of chronic and acute inflammatory conditions.

These and still further objects, as shall hereinafter ap pear, are fulfilled by the present invention to a remarkably unexpected extent as shall become apparent from a consideration of the following description of embodiments exemplifying the invention.

The invention is predicated upon our discovery of 6- cycloalkylguanamines of the type indicated and upon our further discovery that our novel chemical compounds can be formulated into unique medicinal preparations having potent anti-inflammatory activity and which, when compared with known preparations for treating chronic and acute inflammatory conditions, have an unexpectedly reduced incidence of side effects.

The 6-cycloalkylguanamines of the present invention are characterized by unsubstituted amino groups in the 2 and 4 positions and a cycloalkyl group in the 6 position. They may be called 2,4-diamino-6-cycloalkyl-s-triazines,

In one practice of this invention, 6-cycloalkylguanamine, for instance, 6-cyclohexylguanamine, may be synthesized by the catalytic hydrogenation of 6-(3cyclohexenyl) guanamine.

Alternatively, a 6-cycloalkylguanamine having the desired cycloalkyl substitution may be prepared by reacting the corresponding substituted cycloalkyl cyanide with dicyandiamide in the presence of ethylene glycol monomethyl or monoethyl esther and a basic catalyst such as potassium hydroxide at reflux temperatures (e.g., 105- 130 C.) for about 3 to 7 hours. The solvent is then removed from the reaction, as by vacuum distillation, and the residue is collected as by fi-ltration and solubilized in a concentrated mineral acid. The resulting solution is then filtered and the filtrate neutralized to pH 8-9 and cooled. As the solution cools, the 6-cycloalkylguanamine precipitates, and this precipitate may be collected and purified, using conventional techniques. The resulting 6-cycloalkylguanamine is a white crystalline solid. The 6-cycloalkylguanamine is rendered water-soluble by converting it to its acid-addition salt upon reaction with a non-toxic mineral acid such as hydrochloric, sulfuric, phosphoric and the like.

Compounds illustrative of the invention are listed below in Table I.

TAB LE I.-6-CYCLOALKYL GUANAMINES A non-toxic pharmaceutically acceptable organic or inorganic acid addition salt of each of the 6-cycloalkylguanamines may be used in lieu of the guanamine in the practice of the therapeusis of this invention. For example, the salt derived from reacting 6-cycloalkylguanamine with such acids as hydrochloric, sulfuric, nitric, phosphoric, citric, acetic, malonic, lactic, tartaric, sulfamic, succinic, fumaric, maleic, ethanedisulfonic, hydrobromic, benzoic and similar non-toxic acids are suitable to use in the practice of the invention.

To formulate the novel compounds into a pharmaceutical preparation, the 6-cycloalkylguanamine ingredient will be present in an amount sufficient to produce an antiinflammatory effect. In preparations to be administered orally, pancavally and other than at the actual situs of inflammations, that is, by systemic administration, the guanamine is admixed with a pharmaceutically acceptable excipient which may be either solid or liquid. Suitable solid carriers include lactose, magnesium stearate, sucrose, talc, stearic acid, gelatin, agar pectin, acacia and the like. Suitable liquid carries include the glycols, the polyglycols,

dimethyl sulfoxide, peanut oil, olive oil, sesame oil, Water and the like. If desired, the carrier or diluent may also include a time delay material such as glycerol monostearate or glycerol distearate, either alone or with wax.

A Wide variety of pharmaceutical forms can be employed. Thus, when a solid carrier is employed the preparation can be formed into a tablet, a troche, a pastille or a lozenge or it can be pulverized into a powder which may, if desired, be loaded into hard gelatin capsules. The amount of solid carrier will vary according to the form selected and is well within the ordinary skill of the artisan.

When a non-solid carrier is used, the preparation may be used in the form of a soft gelatin capsule, a liquid suspension, an emulsion, an ointment, a suppository or a solution. The amount of non-solid carrier per dose is notocritical and may be adjusted to suit convenience. This form of the preparation can be administered orally, topically, intravenously, or pancavally, the carrier being preselected according to the route of administration desired.

All of the various dosage forms of these preparations can be made by following such of the conventional and well-known manufacturing techniques of mixing, grinding, granulating, compressing, suspending and dissolving as may be deemed appropriate to the desired end product.

The method of using these preparations in accordance with this invention comprises administering to a patient aflicted with the inflammatory condition, 6-cycloalkylguanamines or a non-toxic organic or inorganic acid addition salt thereof, preferably combined with a nontoxic pharmaceutical carrier of the type disclosed in amount to produce an anti-inflammatory effect. As with prior therapeutic agents, the amount required in each case must of necessity be subjective and take into account the diagnosis of the cause of the inflammation, the medical history of the patient and the like. The active medicament in dosage units in most cases will be suflicient to provide a convenient oral or pancaval daily regimen by administering from about 10 mg. to about 2400 mg. per day, advantageously from about 50 mg. to about 800 mg. per day. As indicated previously, administration to the direct situs of inflammation requires substantially less medicament to achieve the desired result.

Thus, the administration of the preparation to the patient may be intramuscularly, parenterally, topically, pancavally, or orally, the latter being the preferable rout of administration. Pancavally as used herein defines administration via all of the bodys openings whether natural such as the vagina, the anus, the nares, or artificial, e.g., colostomy.

In a practice of the invention, when systemic administration as indicated, the preparation is preferably administered orally one to four times daily to provide a daily regimen of from about 10 mg. to about 2400 mg. of active medicament, advantageously from about 50 mg. to about 800 mg.

When local administration is indicated, the preparation is preferably administered topically or interarticularly and can contain as little as 1 mg. of active medicament per dose, depending on the specific condition being treated.

When the administration described above is carried out, the anti-inflammatory action is produced rapidly and eflectively. This method of producing antiinflammatory action by this invention is particularly effective when applied to human beings having rheumatoid diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, gouty arthritis, fibromyositis, osteoarthritis and bursitis. The method is also useful in the the treatment of collagen diseases such as scleroderma, lupus erythmatosus disseminatus and in treating other inflammatory conditions as are associated with allergic bronchial asthma, pulmonary emphysema, pulmonary fibrosis, in. fection, tissue injury and the like.

The preparations are also effective in the treatment of inflammatory conditions accompanying intractable hay fever (pollinosis); skin disorders including atopic dermatitis (eczema), contact dermatitis, poison ivy dermatitis, neurodermatitis, dermatitis herpetiformis, angioedema, urticaria, and exfoliative dermatitis; pemphigus; inflammatory eye diseases including keratitis, allergic conjunctivitis, non-granulomatous iritis, iridocyclitis, chloroditis, uveitis, chlorioetinitis, marginal corneal ulcers and secondary glaucoma complicating inflammatory eye diseases; nephrotic syndrome; and adrenogenital syndrome.

The following examples are presented to aid in providing a clearer understanding of the present invention and of the pharmaceutical compositions therein involved and they are not intended to be limiting in any way.

Example I 6-cyclopropylguanamine is prepared by forming a mixture of 7.37 grams (0.11 mole) of cyclopropyl cyanide, 23.4 grams (0.26 mole) of dicyandiamide, 1.16 grams of 85% potassium hydroxide pellets, and 100 ml. of ethylene glycol monomethyl ether. The mixture is then refluxed and stirred for about 6 hours. The ether solvent is then removed by distillation under vacuum, and the residue is washed with 50 ml. of water. The insoluble product is thereafter collected by filtration, and the filter cake is dissolved in a solution of 150 ml. of water and ml. of concentrated hydrochloric acid. The solution is then filtered and the filtrate is neutralized to pH 89 by the addition of concentrated ammonium hydroxide. The precipitate is then collected by filtration, washed with water, and dried in a vacuum oven to yield 20.0 grams of white solid. The solid is then recrystallized from 50% aqueous methanol to yield 11.6 grams of 6-cyclopropylguanamine (2,4-diamino 6-cyclopropyl-s-triazine) which melts at 296-8 C.

Analysis-Calculated for C H N C, 47.65; H, 6.01; N, 45.33; Found: C, 47.80; H, 5.98; N, 46.30.

Example II 6-cyclobutylguanamine is prepared by following the procedure of Example I, while employing 6.8 grams (0.05 mole) of cyclobutyl cyanide, 6.5 grams (0.077 mole) of dicyandiamide, 1.10 grams of 85% potassium hydroxide pellets, and 95 ml. of ethylene glycol monoethyl ether. 10.0 grams of 6-cyclobutylguanamine (2,4- diamino-6-cyclobutyl-s-triazine) is obtained after recrystallization from 50% aqueous methanol. The product melts at 238.41 C.

Analysis.-Calculated for C H N C, 50.89; H, 6.71; N, 42.39. Found: C, 50.86; H, 6.60; N, 42.39.

Example III 6-cyclopentylguanamine is prepared by forming a mixture of 20.0 grams (0.22 mole) of cyclopentyl cyanide, 9.25 grams (0.11 mole) of dicyanidiamide, 1.16 grams of 85% potassium hydroxide pellets and 100 ml. of ethylene glycol monethyl ether. The mixture is refluxed, with stirring, for 6 hours. The solvent is removed by distilla tion under vacuum, and the residue is Washed with 50 ml. of water. The insoluble product is then collected by filtration and washed with cold water. The filter cake is next recrystallized from 50% aqueous methanol to obtain 6-cyclopentylkuanamine (2,4-diamino-6-cyclopentyls-triazine) (14.9 grams), which melts at ISO-3 C.

Analysis-Calculated for C H N C, 53.02; H, 8.34; N, 38.64. Found: C, 52.88; H, 8.44; N, 38.74.

Example IV 6-(1'-cyclohexenyl)guanamine is prepared by following the procedure of Example III, while employing 23.6 grams (0.22 mole) of l-cyanocyclohexene in place of cyclopentyl cyanide. 6(1'-cyclohexenyl)guanamine (11.4 grams) obtained and upon recrystallization, melts at 257-61 C.

6 Analysis.-Calculated for C H N C, 56.53; H, 6.85; N, 36.62. Found: C, 56.65: H, 6.95; N, 36.48.

Example V 6-(3'-cyclohexenyl)guanamine is prepared by following the procedure of Example III, and employing 23.6 grams (0.22 mole) of 3-cyanocyclohexene. 6(3-cyclohexenyl)guanamine obtained and upon recrystallization, melts at 1968 C.

Analysis.Calculated for C H N C, 56.53; H, 6.85; N, 36.62. Found: C, 56.73; H, 6.93; N, 36.75.

Example VI 6-cyclohexylguanamine is prepared by forming a mixture of 5.74 grams (0.03 mole) of 6-(3-cyclohexenyl)- guanamine, 0.2 grams of platinum oxide catalyst and 50 ml. of glacial acidic acid. The mixture is then hydrogenated under 3 atmospheres of hydrogen until the calculated amount of hydrogen is taken up. Next, the mixture is heated to dissolve the product and filtered to remove the catalyst. The solvent is then removed by distillation under vacuum and, after recrystallization of the residue from water, the 6-cyclohexylguanamine product (1.4 grams) is obtained which, upon recrystallization, melts at 207-9 C.

Analysis.Calculated for C H N C, 55.94; H, 7.82; N, 36.24. Found: C, 55.85; H, 7.63; N, 36.20.

Example VII 6-cycloheptylguanamine is prepared by forming a mixture of 25.0 grams (0.20 mole) of cycloheptyl cyanide, 8.58 grams (0.102 mole) of dicyandiamide, 2.10 grams of potassium hydroxide pellets and ml. of ethylene glycol monomethyl ether. The mixture is refluxed with stirring. At two hour intervals, 4.29 grams (0.051 mole) of dicyandiamide and 2.18 grams (0.026 mole) of dicyandiamide are added. Stirring under reflux is continued for a total of 6 hours. The solvent is then removed by distillation under vacuum, and the residue is washed with 50 ml. of water. The precipitate is then collected by filtration, and the filter cake is recrystallized from 50% aqueous ethanol. The 6 cycloheptylguanamine (20.3 grams) product melts at 208-10 C.

Analysis.-Calculated for C H N C, 57.92; H, 8.25; N, 33.80. Found: C, 57.90; H, 8.61; N, 34.38.

Example VIII 6-(2' -norbornyl)guanamine is prepared by following the procedure of Example III and employing 26.7 grams (0.22 mole) of Z-cyanonorbornane. The 6-(2'-norbornyl)guanamine is obtained and, upon recrystallization, melts at 20810 C.

Analysis.-Calculated for C H N C, 58.51; H, 7.37; N, 34.12. Found: C, 58.42; H, 7.32; N, 34.23.

Example IX 6(2'-trans-phenylcyclopropyl)guanamine is prepared by the procedure of Example I, when 15.7 grams (0.11 mole) of trans-1-cyano-2-phenylcyclopropane is used in lieu of cyclopropyl cyanide. The 6-(2'-trans-phenylcyclopropyl)guanamine product (18.5 grams) is obtained and, upon recrystallization, melts at 194-5 C.

Analysis.Calculated for C H N C, 63.41; H, 5.76; N, 30.81. Found: C, 63.61; H, 6.00; N, 31.04.

Example X To prepare an acid addition salt, 50 grams of 6-cyclopentylguanamine (2,4-diamino-6-cyclopentyl-1,3,5 triazine) was prepared according to Example I and then dissolved into a mixture of 30 ml. concentrated hydrochloric acid and 1 liter of anhydrous 3A ethanol on a hot plate with stirring. The solution was then filtered by gravity and the filtrate was cooled in the refrigerator. The crystaline hydrochloride was collected by filtration in a Buchner funnel and dried in a vacuum oven to yield 41.4 g. M.P. 2958 C., dec.

7 The filtrate from above was concentrated on a rotary evaporator to approximately 400 ml. and cooled once more. The second crop was collected by filtration and dried, as before, to yield an additional 14.0 g. of the hydrochloride, M.P. 293-6 0, dec.

Example XI Two hundred mg. of 6-cyclopropylyguanamine, mg of sorbitol and 85 mg. of mannitol were milled to uniform powder and granulated into 6 mg. of gelatin as a 10% solution. The mixture was then screened onto trays and dried 60 C., the dried granules were then sized and mixed with mg. of cornstarch and 4 mg. of magnesium stearate. The mixture was then compressed into tablets.

Example XII Ingredients: Weight mg. 6-cyclopentylguanamine hydrochloride 200 Avicel (microcrystalline cellulose) 150 Polyvinyl pyrrolidone 5 Magnesium stearate 4 The first three ingredients were mixed to uniformity and lubricated with a portion of the magnesium stearate. The mixture was compressed into slugs, and the slugs were reduced to uniformity and granulated. The powder was then lubricated with the remainder of the magnesium stearate and compressed into tablets.

Example XIII Ingredients: Weight mg. 6-cyclopentylguanamine 200 Lactose 175 Magnesium stearate 5 The above ingredients were screened through a U.S. mesh screen or mill to a uniform powder, transferred to a mixer, mixed Well and filled into #1 hard gelatin capsules.

Example XIV Ingredients: Weight mg. 6-cyclopropylguanamine Sesame oil 50 The ingredients are mixed into a thick slurry and filled into soft gelatin capsules.

Example XV Ingredients: Weight mg. 6-cyclopentylguanamine hydrochloride 300 Polyethylene Glycol 400 240 The ingredients are mixed into a thick slurry and filled into soft gelatin capsules.

Example XVI Ingredients Weight 6-cyclobutylguanamine 200 gms. Polyethylene Glycol 200 q.s. up to 1 liter The ingredients are added together and warmed to about 50 C. C. to effect solution and stirred. The solution was then sterile filtered, cooled to room temperature, packaged in sterile vials and stored until needed.

Example XVII A suppository having a melting point of about 60 F. was prepared having the following ingredients in the amounts indicated:

Ingredients: Amount mgs. 6-cyclohexylguanamine 200 Polyethylene Glycol 600 200 Polyethylene Glycol 4000 800 The ingredients were mixed together and heated to about 60 C. to effect solution. The solution was then poured into cooled molds and permitted to cool and solidify.

Example XVIII An ointment embodying the present invention was prepared from the following ingredients in the amounts indicated:

Ingredients: Amount mgs. 6-cyclopentyl hydrochloride 200 Polyethylene Glycol 1540 500 Polyethylene Glycol 4000 Propylene Glycol 200 Cetyl alcohol 20 Example XIX Each of the compounds listed in Table I was subjected to an anti-inflammatory pharmacological assay using a modification of the Selye Granuloma Pouch assay (Arch. int. Pharmacodyn. 97, 379 (1954), the modification being that Mycobacterium butyricum (adjuvant) was used as the phlogistic agent in place of croton oil. Male rats obtained from Holtzman Company, Madison, Wisconsin and Weighing 220 to 240 grams each, were used throughout the assay. The dorsal area of each animal was shaved with an electric clipper and the animals were placed under light ether anesthesia. The shaved regions were wiped with 70% ethanol, and 25 ml. of air was injected at the approximate center of each animals shaved portion using a syringe and 24 gauge needle.

The phlogistic agent (a killed and dried preparation of Mycobacterium butyricum (was suspended to provide 0.125 mg. of agent in 0.4 ml. sesame oil. This suspension Was then injected using a 22 gauge needle into the formed air pouch at a situs different from that of the air injection. ll syringe needles were immersed in 70% ethanol between uses in successive animals. To insure accurate dosage, the phlogistic-agent suspension was continuously mived with a magnetic stirrer. In all instances, air was removed 48 hours after formatoon of the pouch. The test compounds were triturated in a mortar and pestle with 1% pectin, and the resulting suspension was administered by gavage in a volume of 1 ml./ 100 g. body weight. All test animals were administered test compounds once per day for 4 consecutive days, beginning on the day of pouch formation. The animals were necropsied on the 5th day.

The volume of exudate formed in each animal treated by the drug is then compared with the volume of exudate formed in the untreated control animals. A reduced volume of exudate is an accepted measure of antiinflammatory activity. The relationship of the difference between the volume of exudate in the test animal and that of the control animal compared to the value of the control animal is reported below as Percent Inhibition. The higher this value, the more effective a test compound is as an anti-inflammatory drug.

The results obtained for the compounds of Table I in the foregoing assay are reported in Table II.

TAB LE II.ANTI-INFLAMMATO RY ACTIVITIES O F 6- CYCLOALKYL GUANAMINES N H3 N-- R N Daily D ose Percent Number* R mg. [kg Inhibition 50 92 1 Cyclopropyl 20 66 100 20 54 2 Cyclobutyl 5 55 50 88 20 79 3 Cyclopentyl 10 66 50 88 4 Cyclohexyl 5 1-cyelohexenyl 200 43 0 3-eycl0hexenyl 2g 7 Oycloheptyl 50 45 50 76 8 2-norborny1 20 4 1 10 35 9 Trans-phenylcyclopropyl. 200 87 *The number used corresponds to that set forth in Table I.

9 EXAMPLE XX Additional rat adjuvant air pouch anti-inflammatory activity assays were performed using the protocol described in Example XIX at a variety of dosage levels.

The results obtained are reported in Table III.

TABLE III.-ANTI-INFLAMMATORY ACTIVITIES OF 6- CYCLOALKYLGUANAMINES IIIHz N NHz Percent R Dose, mgJkg. Inhibition y p py 3-eyclohexenyl gg 2 1-cyc1ohexnyl 200 43 200 97 50 80 50 94 50 90 50 89 50 81 2O 63 Cyclopentyl 20 48 20 74 20 46 10 62 10 19 10 42 10 36 34 5 23 200 96 100 86 50 76 2-norb0rny1 20 41 20 49 35 10 2 200 97 1h 1 28 3% 0 00 ex y y 54 10 a O clohe t l 50 y p y 100 95 Cyclobutyl $8 2% 5 55 (2-trans-phenylcyclopropyl) 200 87 2-ketocyclohexyl 200 58 50 74 50 83 Cyclopentyl hydrochloride 20 50 1 11-1 N ra \N wherein R is a cycloalkyl radical having from 3 to 5 carbon atoms.

2. A compound according to claim 1 denominated 6- cyclopropylguanamine.

3. A compound according to claim 1 denominated 6- cyclobutylguanamine.

4. A compound according to claim 1 denominated 6- cyclopentylguanamine.

References Cited UNITED STATES PATENTS 2,305,217 12/1942 Durant 260--249.9 XR 2,385,765 9/1945 Thurston, 260249.9 XR

2,527,314 10/1950 Mackay 260249.9 2,859,188 11/1958 Heidler et al. 260249.9 XR

HENRY R. JILES, Primary Examiner J. M. FORD, Assistant Examiner US. 01. X.R. 424 249 

